Chiral expoxides or chiral 1,2-diols have been widely used to prepare pharmaceuticals, agriculture products and food additives having optical properties (U.S. Pat. No. 5,071,868; Tetrahedron Lett., Vol. 28, No. 16, 1783, 1987; J. Org. Chem., Vol. 64, 8741, 1999). Even if these chiral epoxides or chiral 1,2-diols having high optical purity are very useful compounds industrially, use of these compounds has been restricted because the preparation of such compounds is too difficult to produce in a large scale with low manufacturing price and the optical purity, which is an important factor in determining the quality of products, is insufficient. Because enantiomers have radically different biological activity, the FDA has stated that “compounds having the same structure and composition are treated as different compounds if they are optical stereoisomers” so that pharmaceutical feedstocks, and fine chemical feedstocks must be produced with utmost concern for the chirality of the molecules. Generally, the chirality of the molecules having higher than 99.5% is acceptable for the pharmaceutical feedstocks, fine chemical feedstocks, and foods additives.
A preparation method of chiral epichlorohydrins as one of chiral expoxides is disclosed using microorganism in EP Patent No. 431,970 and JP Patent Publication Nos. 90-257895 and 94-211822. However, it is not recommended because the productivity is low and it, further, requires more than two-step process. Another preparation method of chiral epichlorohydrins from chiral sulfonyloxyhaloalcohol derivatives obtained from mannitol derivatives is disclosed in U.S. Pat. No. 4,408,063; and J. Org. chem., Vol 43, 4876, 1978. Another preparation method of chiral epichlorohydrins from 3-chloro-1,2-propanediol is also disclosed in Syn. Lett No. 12, 1927, 1999. However, these processes are required multi-step syntheses, so that they are also deficient to use for the industrial purpose.
Methods for preparing chiral expoxides generally use a chiral catalyst having stereoselectivity which hydrolyzes stereoselectively only one isomer from racemic epoxides mixed 50 and 50 of each isomer and leaves the un-hydrolyzed isomer in the reaction medium. However, the chiral catalyst used for said stereoselective hydrolysis is required to be economical, have high stereoselectivity and be re-usable without employing activation process, thus suitable for the industrial purpose.
Stereoselective hydrolyses of chiral epoxides using chiral salen catalyst as a chiral catalyst are recently disclosed in Science, Vol. 277, 936, 1997; U.S. Pat. Nos. 5,665,890, 5,929,232, 5,637,739, and 5,663,393; and WO00/09463 and WO91/14694. It has been reported that the use of chiral salen catalyst provides higher yield with higher optical purity compared to uses of other chiral catalysts.
However, it is reported that after hydrolysis of racemic epoxide using said chiral salen catalyst, the product chiral epoxide is racemized as time goes in pages 86-87 of WO00/09463. The hydrolysis of racemic epoxides is performed by employing said chiral catalyst and water to hydrolyze stereoselectively only one isomer from R and S isomers. The unhydrolyzed chiral epoxide is isolated from the reaction medium. During the purification process to isolate the desired chiral epoxide, the racemization is caused by the side reaction of hydrolyzed product (chiral 1,2-diol) due to instability of the chiral salen catalyst. Therefore, this method also has a fatal drawback for mass-production of chiral compounds.
When this hydrolysis is performed for mass production, the racemization of the product becomes deepened since it takes longer to perform the distillation to obtain the desired product, thus resulting in decrease of optical purity of the chiral epoxide. Therefore, the use of chiral salen catalyst in the production of chiral epoxides is limited for the above-mentioned reasons.
Further, when conventional chiral salen catalysts are reused, it requires an activation process after each use because activities thereof are rapidly decreased. Even if the catalyst is activated after used, the optical activity of the product prepared by using reused catalyst is remarkably lower than that of the product prepared by using fresh catalyst. Thus, there is limited to reuse. Such problems increase the manufacturing price of producing chiral epoxides.
Consequently, demand to produce chiral compounds such as chiral epoxides or chiral 1,2-diols efficiently and economically has been highly increased with the importance of such compounds to prepare pharmaceuticals and agriculture products.
Especially, in preparing chiral medicines or chiral intermediates, it is very difficult or almost impossible to further increase the optical purity of the same product once it is prepared, or to remove undesired optical stereoisomer, unlike the chemical purity. Thus, the technique for preparing chiral compounds having a high optical purity, which is sufficient for the materials for medicines, in the present invention is distinct, efficient and different from the preparation techniques which only focus on heightening the ratio of the desired stereoisomer in the racemic compounds.